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CD40/CD154 Interactions Are Required for the Optimal Maturation of Skin-Derived APCs and the Induction of Helminth-Specific IFN- but Not IL-4¹

James P. Hewitson^*, Gavin R. Jenkins^*, Paul A. Hamblin and Adrian P. Mountford^2,*

^* Department of Biology, University of York, York, United Kingdom; and Biopharmaceutical Center for Excellence in Drug Discovery, GlaxoSmithKline, GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom

The mechanisms through which Schistosoma mansoni larvae induce Th1 rather than Th2 immune responses are not well understood. In this study, using CD154^–/– mice exposed to radiation-attenuated S. mansoni larvae, we demonstrate roles for CD154/CD40 in the activation of skin-derived APCs and the development of Th1 cells in the skin-draining lymph nodes (sdLN). The presence of CD154 was important for optimal IL-12p40 and essential for Ag-specific IFN-, but CD154 expression by wild-type CD4^– cells was insufficient to rescue recall responses of CD4⁺ cells from CD154^–/– mice. This defect is probably due to impaired CD40-dependent IL-12 production in vivo, because administration of anti-CD40 Ab, or rIL-12, restored IFN- production by sdLN cells from CD154^–/– mice. CD154 ligation of CD40 was not required for the migration of skin-derived APCs, but did have a limited role in their maturation (increased MHC II and CD86). Unexpectedly, although CD4 cells from CD154^–/– mice were deficient in their ability to produce IFN-, they produced significant amounts of IL-4 and IL-5 in the presence of skin-derived APCs from wild-type and CD154^–/– mice. Thus, in contrast to IFN-, the production of Th2-associated cytokines is (in this model) independent of CD154. We conclude that whereas the priming of Th1 responses soon after exposure to schistosome larvae is completely CD40/CD154 dependent, IL-4, IL-5, and IL-13 are independent of CD154, suggesting a dichotomy in the specific mechanisms that induce these cytokines by CD4⁺ cells in the sdLN.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ J.P.H. was supported by a Ph.D. studentship from the Biotechnology and Biological Sciences Research Council of the United Kingdom and a Co-Operative Award in Science and Engineering studentship from GlaxoSmithKline. This work was also supported by a Wellcome Trust University Fellowship to A.P.M. (056213) and a Wellcome Trust Project Grant (071762).

² Address correspondence and reprint requests to Dr. Adrian P. Mountford, Department of Biology (Area 5), University of York, York YO10 5YW, U.K. E-mail address: apm10{at}york.ac.uk

³ Abbreviations used in this paper: sdLN, skin-draining lymph node; DEC, dermal exudate cell; cRPMI, complete RPMI; RA, radiation attenuated; SSAP, soluble schistosomula Ag preparation; WT, wild type.

This article has been cited by other articles:

				J. P. Hewitson, P. A. Hamblin, and A. P. Mountford In the Absence of CD154, Administration of Interleukin-12 Restores Th1 Responses but Not Protective Immunity to Schistosoma mansoni Infect. Immun., July 1, 2007; 75(7): 3539 - 3547. [Abstract] [Full Text] [PDF]